Clinical features and management of germline CEBPA-mutated carriers.

Familial acute myeloid leukemia (AML) pedigrees with germline CCAAT/enhancer-binding protein-α (CEBPA) mutation have been rarely reported due to insufficient knowledge of their clinical features. Here, we report two Chinese families with multiple AML cases carrying germline CEBPA mutations, one of which had 11 cases spanning four consecutive generations. Additionally, we collected clinical data of 57 AML patients from 22 families with germline CEBPA mutations, with 58.3% of them harboring double CEBPA mutations. The first mutation frequently occurred at the N-terminal of CEBP/α (78.6%), resulting in an exclusive expression of p30 of CEBPA (CEBPAp30). The second mutation was mostly found at the C-terminal of CEBP/α (CEBPAothers). Germline CEBPAp30 carriers had higher incidences of AML (80.36% vs. 42.86%) and earlier onset of AML (18 vs. 38.5 years old) compared to germline CEBPAothers carriers. Despite the high rates of relapse, most familial AML cases exhibited favorable overall survival (OS), with germline CEBPAp30 carriers having better survival outcomes (>25 years vs. 11 years for CEBPAothers carriers). Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.

Sm and Gd Contacts in 2D Semiconductors for High-Performance Electronics and Spintronics.

Two-dimensional (2D) semiconductors have attracted great attention due to their rich electronic properties and even been considered to have the potential to extend Moore's Law. However, the Schottky barrier between the metal and 2D semiconductor is formed due to the metal-induced gap states (MIGS), which greatly hinder the development of 2D semiconductor transistors in large-scale integrated circuits. Meanwhile, most air-stable 2D semiconductors are nonmagnetic, limiting the possibility of spintronic application. Here, we report a new strategy to suppress the MIGS and reduce the Schottky barrier height on 2D semiconductors (MoS2, WS2, and WSe2) by using lanthanide metal (Sm and Gd) contacts. It was found the lanthanide contacts exhibit a good Ohmic property with a near-zero Schottky barrier. As a result, the carrier mobility of MoS2 transistors reaches 118 cm2/(V s). Furthermore, Gd-contact MoS2 transistors show the typical magnetic property where the magnetoresistance reaches 2.7% at 5 K. By studying its spin valve effect, it was demonstrated that the nonlocal magnetoresistance is 4.1% and spin polarization is 3.25%. This study provides a promising pathway for high-performance 2D electronic and spintronics, which may open a new strategy for future computing-in-memory architecture.

A life-threatening bleeding prediction model for immune thrombocytopenia based on personalized machine learning: a nationwide prospective cohort study.

Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.

Recombinant GM-CSF enhances the bactericidal ability of PMNs by increasing intracellular IL-1ß and improves the prognosis of secondary Pseudomonas aeruginosa pneumonia in sepsis.

This study tested the hypothesis that recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances polymorphonuclear neutrophils (PMNs) via interleukin (IL)-1ß to improve the prognosis of secondary infection in sepsis. The latter stage of sepsis is prone to induce immunosuppression, resulting in secondary fatal infections. Recombinant GM-CSF has become a way for sepsis-induced immunosuppression due to its immunomodulatory effect. However, the functional impact of GM-CSF on PMNs in sepsis remains obscure. This study aimed to study the role of recombinant GM-CSF on the bactericidal ability of PMNs in septic mice, assessing its effect on the prognosis of secondary pneumonia, and explore the mechanism of recombinant GM-CSF by intervening PMNs in patients with sepsis. The C57BL/6J sepsis mouse model was induced by cecal ligation and puncture. Recombinant murine GM-CSF (rmGM-CSF) was used in vivo when mice developed immunosuppression, which was characterized by abnormal bactericidal function of PMNs in peripheral blood. rmGM-CSF improved the prognosis of secondary pneumonia and reversed the function of PMNs. PMNs isolated by Percoll from septic patients were treated by recombinant human GM-CSF (rhGM-CSF) in vitro. The expression of CD11b, reactive oxygen species, phagocytosis, and neutrophil extracellular trap release in PMNs were enhanced by rhGM-CSF treatments. Whole-transcriptomic sequencing of mouse PMNs indicated that recombinant GM-CSF increased the expression of Il1b gene in PMNs. Blocking and inhibiting IL-1ß release effectively counteracted the enhancing effect of GM-CSF on the bactericidal function of PMNs. rmGM-CSF enhances the bactericidal function of PMNs in vivo and improves the prognosis of secondary pneumonia in septic mice, and recombinant GM-CSF increases IL-1ß precursor reserves, which, if stimulated, can rapidly enhance the bactericidal capacity of PMNs.

A case of a common bile duct stone containing a metallic clip appearing after laparoscopic cholecystectomy.

Laparoscopic cholecystectomy (LC) is currently the standard procedure for the treatment of benign gallbladder diseases. Although the ligature clip may fall off and shift after surgery, relevant reports are rare. We describe the formation of common bile duct stone in an elderly female in which a metal clip displaced into the common bile duct 6 years after LC.

Dhx15 regulates zebrafish intestinal development through the Wnt signaling pathway.

DEAH-box helicase 15 (DHX15) is ATP-dependent RNA helicase which is known for its role in RNA metabolism. Recent studies reported DHX15 involves in the intestinal immunity. However, the role of DHX15 (or RNA helicase) in intestinal development is poorly understood. Here, we revealed an unidentified role for dhx15 in regulating zebrafish intestinal development. We found the profound intestinal defects in dhx15 knockout zebrafish. Decreased proliferation and increased apoptosis of the intestine cells were observed when dhx15 were deleted. Further RNA genome wide analysis and qRT-PCR analysis showed the Wnt signaling pathway is down-regulated in the dhx15 knockout zebrafish. Thus, we concluded that dhx15 regulates zebrafish intestinal development through the Wnt signaling pathway. Here, we provided new insights into the role of dhx15 in intestinal development beyond its well-characterized role in intestinal immunity.

Strong Anisotropic Two-Dimensional In2Se3 for Light Intensity and Polarization Dual-Mode High-Performance Detection.

Detecting the light from different freedom is of great significance to gain more information. Two-dimensional (2D) materials with low intrinsic carrier concentration and highly tunable electronic structure have been considered as the promising candidate for future room-temperature multi-functional photodetectors. However, current investigations mainly focus on intensity-sensitive detection; the multi-dimensional photodetection such as polarization-sensitive photodetection is still in its early stage. Herein, the intensity- and polarization-sensitive photodetection based on α-In2Se3 is studied. By using angle-resolved polarized Raman spectroscopy, it is demonstrated that α-In2Se3 shows an anisotropic phonon vibration property indicating its asymmetric structure. The α-In2Se3-based photodetector has a photoelectric performance with a responsivity of 1936 A/W and a specific detectivity of 2.1 × 1013 Jones under 0.2 mW/cm2 power density at 400 nm. Moreover, by studying the polarized angle-resolved photoelectrical effect, it is found that the ratio of maximum and minimum photocurrent (dichroic ratio) reaches 1.47 at 650 nm suggesting good polarization-sensitive detection. After post-annealing, α-In2Se3 in situ converts to ß-In2Se3 which has similar in-plane anisotropic crystallinity and exhibits a dichroic ratio of 1.41. It is found that the responsivity of ß-In2Se3 is 6 A/W, much lower than that of α-In2Se3. The high-performance light intensity- and polarization-detection of α-In2Se3 enlarges the 2D anisotropic materials family and provides new opportunities for future dual-mode photodetection.

Asymmetric effects of economic policy uncertainty and environmental policy stringency on environmental quality: evidence from China and the United States.

The importance of economic policy uncertainty (EPU) and environmental policy stringency (EPS) in affecting environmental quality is gaining great attention in the literature. However, none of the existing studies has thought to investigate their combined effects on carbon dioxide (CO2) emissions. Additionally, the individual investigations into the nexuses EPU-emissions and EPS-emissions primarily took a symmetric assumption between these variables into consideration. The current paper is an early attempt to close these gaps by examining the combined effects of economic policy uncertainty and environmental policy stringency on CO2 emissions within asymmetric (nonlinear) frameworks in China and the United States (US). The empirical findings indicate that an improvement in EPU degrades the environmental quality in both countries. However, a negative shift in EPU decreases emissions in China while increasing them in the US. In terms of EPS, the estimates in the two nations led to similar results. A positive change in EPS is conducive to fewer emissions, whereas a negative change worsens environmental damage. These findings still hold with the sensitivity analysis using ecological footprint as an alternative gauge of environmental destruction. This study, therefore, suggests that both nations adopt stricter environmental policies. Additionally, Chinese policymakers should work to lessen uncertainty shocks, while the US government should promote more transparent economic policies.

Targeting transmembrane-domain-less MOG expression to platelets prevents disease development in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system with no cure yet. Here, we report genetic engineering of hematopoietic stem cells (HSCs) to express myelin oligodendrocyte glycoprotein (MOG), specifically in platelets, as a means of intervention to induce immune tolerance in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. The platelet-specific αIIb promoter was used to drive either a full-length or truncated MOG expression cassette. Platelet-MOG expression was introduced by lentivirus transduction of HSCs followed by transplantation. MOG protein was detected on the cell surface of platelets only in full-length MOG-transduced recipients, but MOG was detected in transmembrane-domain-less MOG1-157-transduced platelets intracellularly. We found that targeting MOG expression to platelets could prevent EAE development and attenuate disease severity, including the loss of bladder control in transduced recipients. Elimination of the transmembrane domains of MOG significantly enhanced the clinical efficacy in preventing the onset and development of the disease and induced CD4+Foxp3+ Treg cells in the EAE model. Together, our data demonstrated that targeting transmembrane domain-deleted MOG expression to platelets is an effective strategy to induce immune tolerance in EAE, which could be a promising approach for the treatment of patients with MS autoimmune disease.

Blood MALT1 deficiency is common and relates to unfavorable induction therapy response and survival profile in acute myeloid leukemia patients.

BACKGROUND: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) regulates T helper/regulatory T cell balance, autoimmunity development, and leukemia pathogenesis. As a result, this study aimed to investigate the clinical role of MALT1 in patients with acute myeloid leukemia (AML). METHODS: MALT1 expressions were measured in peripheral blood mononuclear cell (PBMC) from 90 newly diagnosed AML patients before and after induction treatment using RT-qPCR. Moreover, MALT1 expressions were also determined in 50 disease controls (DCs) and 50 healthy controls (HCs). RESULTS: MALT1 expression was reduced in AML patients compared to HCs and DCs (both adjusted P < .001). Lower MALT1 expression was related to white blood cells >10×109/L (P = .037) and poor risk stratification (P = .020) in AML patients. MALT1 expression was elevated during induction treatment not only in total AML patients (P < .001), but also in subgroups of patients achieving complete remission (CR) (P < .001) and in those not achieving CR (P = .001). Furthermore, MALT1 expressions before induction treatment (P = .042) and after induction treatment (P < .001) were both increased in AML patients with CR compared to those with non-CR. Interestingly, both pre- and post-treatment MALT1 low (vs. high) were related to shorter accumulating event-free survival (EFS), which was also associated with a reduced accumulating overall survival (OS) (all P < .05). Furthermore, MALT1 increment during induction treatment < 50% was related to unsatisfied accumulating EFS (P = .001) and OS (P = .007). CONCLUSION: PBMC MALT1 deficiency is common and relates to unfavorable induction therapy response and survival profile in AML patients.

RNA helicase DHX15 decreases cell apoptosis by NF-κB signaling pathway in Burkitt lymphoma.

BACKGROUND: DHX15 is one of the RNA helicase family members involving in several biological processes. Studies have reported that overexpression of DHX15 is related to cancer progression. However, the role of DHX15 in Burkitt lymphoma (BL) and latent Epstein-Barr virus (EBV) infection remains to be elucidated. METHODS: Expression of DHX15 was measured in BL patient by immunohistochemical staining. In vitro study, a CCK-8 assay was used to analyze cell proliferation and flow cytometry was performed to assess cell cycle, apoptosis and mitochondria membrane potential. Members of NF-κB signaling pathway and apoptotic-related proteins expression were measured by western-blot. EBV latent infection products and RNA polymerase III transcripts expression were determined by quantitative real-time PCR and western-blot. In vivo study, HE, IHC, TUNEL and ISH assays were used to analyze the effect of DHX15 on subcutaneous tumor nodes formation. RESULTS: DHX15 was overexpressed in Burkitt lymphoma patients and tends to be associated with poor progression-free survival and poor overall survival. Knockdown of DHX15 significantly inhibited BL tumor growth, reduced cell proliferation, induced cell cycle arrest and increased cell apoptosis. Further analysis showed that canonical NF-κB signaling and its downstream targets, mitochondria and Caspase were involved in the increased cell apoptosis after DHX15 gene knockdown. Furthermore, knockdown of DHX15 reduced EBV latent infection products expression and inhibited RNA polymerase III activity. CONCLUSION: DHX15 may be an oncogene in the development of BL and a potential therapeutic target for the treatment of BL and latent EBV infection.

3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia.

Sphingolipids and their metabolic pathways have been implicated in disease development and therapeutic response; however, the detailed mechanisms remain unclear. Using a sphingolipid network focused CRISPR/Cas9 library screen, we identified an endoplasmic reticulum (ER) enzyme, 3-Ketodihydrosphingosine reductase (KDSR), to be essential for leukemia cell maintenance. Loss of KDSR led to apoptosis, cell cycle arrest, and aberrant ER structure. Transcriptomic analysis revealed the indispensable role of KDSR in maintaining the unfolded protein response (UPR) in ER. High-density CRISPR tiling scan and sphingolipid mass spectrometry pinpointed the critical role of KDSR's catalytic function in leukemia. Mechanistically, depletion of KDSR resulted in accumulated 3-ketodihydrosphingosine (KDS) and dysregulated UPR checkpoint proteins PERK, ATF6, and ATF4. Finally, our study revealed the synergism between KDSR suppression and pharmacologically induced ER-stress, underscoring a therapeutic potential of combinatorial targeting sphingolipid metabolism and ER homeostasis in leukemia treatment.